Ciliopathies
Cilia are evolutionarily conserved eukaryotic organelles that extend from, and are continuous with, the cell membrane. Nearly all-mammalian cells form cilia, and the ciliary apparatus is connected to cell cycle progression and proliferation. Cilia comprise a microtubular backbone (the ciliary axoneme), which is surrounded by plasma membrane and is nucleated and organized by the basal body, located at the base of cilia (Figure 1). Cilia can be broadly subdivided into motile, characterized by a typical ’9+2’ architecture with nine outer microtubule doublets and a central pair of microtubules (e.g bronchi) and primary, which appear typically as single appendages on the apical surface of cells and lack the central pair of microtubules (e.g. epithelium of kidney tubules). Ciliary proteins are synthesized in the cell body and must be transported to the tip of the axoneme. This is achieved by Intraflagellar Transport (IFT), an ordered and highly regulated anterograde and retrograde translocation of polypeptide complexes (IFT particles) along the length of the ciliary axoneme.
Cilia dysfunction has been implicated in a wide spectrum of genetic disorders such as Bardet-Biedl (BBS), Joubert, Meckel, Alstrom and Oral-facial-digital type I (OFDI) syndromes, which are all characterized by the presence of cystic kidneys associated with additional extrarenal symptoms. Interestingly, the protein products encoded by the genes responsible for inherited forms of cystic kidneys such as autosomal dominant (ADPKD) and, autosomal recessive polycystic kidney diseases (ARPKD), and Nephronophthisis (NPHP) are all expressed in primary cilia, basal bodies, or centrosomes suggesting that ciliary dysfunction might be the unifying pathogenic concept underlying cystic kidney disease.
Figure 1. Representation of the microtubule continuum extending from the nucleus to the ciliary tip. Schematic representation of the cilium as a signaling device through which different external signals (Wnt, Shh, mechanical, and possibly others) are sensed and transduced into the cell, ultimately reaching the nucleus to affect gene regulation, cell division, and differentiation.
[Taken from Badano JL, Mitsuma N, Beales PL, Katsanis N (2006). The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7: 125-148].
